Acne vulgaris can negatively impact a patient's quality of life. This study evaluated the psychological and interpersonal perceptions of patients who had received acne treatment. Using data from the National Institutes of Health's All of Us Research Program, we analyzed survey responses from 1,843 participants treated with systemic therapies for acne (reflecting more severe disease) and 1,843 matched participants treated with topical therapies alone. Outcomes included surveys assessing both mental and social health and the prevalence of neuropsychiatric conditions between groups. Compared with those who used only topical therapies, participants treated with systemic therapies for acne experience greater personal and relational difficulties in addition to having higher rates of obsessive-compulsive disorder, personality disorders, anxiety, and depression. These findings were robust in a sensitivity analysis excluding isotretinoin-treated participants. The subset of people with acne who receive systemic therapy comprise a high-risk group for adverse psychological outcomes. We aim to bring greater awareness and sensitivity to these issues among dermatologists and other clinicians managing acne. We also aim to highlight the potential need for neuropsychiatric support in patients with more severe acne.